Targeting unfolded protein response: a new horizon for disease control

Abstract

Unfolded protein response (UPR) is an evolutionarily conserved pathway triggered during perturbation of endoplasmic reticulum (ER) homeostasis in response to the accumulation of unfolded/misfolded proteins under various stress conditions like viral infection, diseased states etc. It is an adaptive signalling cascade with the main purpose of relieving the stress from the ER, which may otherwise lead to the initiation of cell death via apoptosis. ER stress if prolonged, contribute to the aetiology of various diseases like cancer, type II diabetes, neurodegenerative diseases, viral infections etc. Understanding the role of UPR in disease progression will help design pharmacological drugs targeting the sensors of signalling cascade acting as potential therapeutic agents against various diseases. The current review aims at highlighting the relevance of different pathways of UPR in disease progression and control, including the available pharmaceutical interventions responsible for ameliorating diseased state via modulating UPR pathways.

Molecular mechanisms of programmed cell death in methamphetamine-induced neuronal damage

“…When stressed, protein folding capacity in the ER decreases, which leads to the accumulation of unfolded and misfolded proteins in the ER, and the unfolded protein response (UPR) takes place to remove these proteins and maintain ER homeostasis ( Go et al, 2017 ). The processes affecting UPR are mediated by protein kinase-RNA-like endoplasmic reticulum kinase (PERK), activating ATF6 as well as inositol-requiring transmembrane kinase/endonuclease 1 (IRE1) ( Khanna et al, 2021 ; Shacham et al, 2021 ; Siwecka et al, 2021 ; van Anken et al, 2021 ). C/EBP homologous protein (CHOP) is known to trigger UPR-dependent apoptosis ( Sano and Reed, 2013 ; Bahar et al, 2016 ).…”

ROS and Endoplasmic Reticulum Stress in Pulmonary Disease

“…After dissociation of GRP78, ER stress receptor proteins are activated to trigger UPR generation, reduce the load of ER by limiting the synthesis of unfold proteins, and trigger their respective induced pro-survival response. The PERK-activated-pro-survival pathway inhibits protein translation and synthesis by limiting the entry of abnormally folded proteins into ER and reducing ER’s pressure for new protein folding ( Borges and Lake, 2014 ; Hetz et al, 2015 ; Khanna et al, 2021 ). PDI (phosphorylation of protein disulfide isomerases), fundamental enzymes involved in ER protein folding, allows these proteins to combine with luminal IRE1 α , then moderating excessive IRE1 α activity to protect against cell injuries induced by maladaptive UPR ( Zhang et al, 2019a ).…”

Endoplasmic reticulum stress targeted therapy for breast cancer

“…ER is the organelle for protein secretion and appropriate protein folding to maintain protein homeostasis [ 8 ]. In the microenvironment of a malignant tumor, the protein folding ability of the ER in cancer cells and infiltrating immune cells changes, which leads to the accumulation of misfolded and unfolded protein [ 9 ]. When the accumulation of misfolded proteins exceeds the tolerable threshold, the three ER sensors will trigger the unfolded protein response (UPR), which results in the activation of a series of complex signaling pathways [ 10 ].…”